Dendritic cells (DC) derive from hematopoietic stem cells (HSC) and develop under the influence of defined growth factors. DCs have an essential role in the initiation of immune responses and in assuring peripheral immune tolerance. Still, the mechanisms that generate these biological outcomes are not known. In addition, few small animal models are currently available to study the biology of human DCs in vivo.
Human Immune System (HIS) mice harboring all three classes of human lymphocytes (B, T, NK cells) can be generated following transfer of human CD34+ HSC to newborn Balb/c Rag2−/−γc−/− mice. While human DCs are observed in HIS mice, their development appears suboptimal and their homeostasis may be perturbed, possibly due to competition with endogenous mouse DCs that develop normally in these recipients. As a result, DC responses in HIS mice are primarily of mouse origin. Since human and mouse DC respond differently during immune responses, a HIS mouse model with a minimal mouse DC compartment and a maximal human DC compartment would be advantageous.
In order to address these shortcomings, the present invention provides an improved HIS mouse model that compromises endogenous mouse DC development and allows for preferential human DC development. HIS mice generated in this new recipient strain, using an exogenous cytokine boost protocol, develop human B, T, and NK cells, but show enhanced human DC development (including both classical CD11c+ DCs as well as CD123+ plasmacytoid DC). Moreover, increased percentages of human CD15+CD33+ myeloid cells and CD14+ monocytes and macrophages could be identified in the spleen and bone marrow of transplanted mice. The human DCs identified in said HIS mice were functional, producing cytokines and soluble inflammatory factors following TLR stimulation. Increased human DC also improved the numbers of human NK and T cells in the recipient HIS mice.